Growth factors and their receptors play a prominent role in inherited human diseases, which range from malformations of bone, vasculature, pigmentation, and digits to abnormalities which contribute to cancer predisposition. During embryonic development, growth factor signals must be precisely controlled in order for normal development to occur. Although growth factors are known to be important in contributing to cell survival and growth, it is not precisely known how they signals trigger and mediate extremely complex structures such as the limb, the lung, the kidney, and the skin. In addition to the normal regulatory controls of the cell to limit overactivity and duration of growth factor signals, other inhibitors of growth factor signaling may actually play a role themselves in direct growth and patterning of complex structures. Recently, a novel family of inhibitors was identified in Drosophila as an important contributor to the complex process of tracheal branching. The inhibitors were thus given the name, Sprouty. The Sprouty gene is evolutionarily conserved and in human, there are four Sprouty genes, Spry1, 2, 3, and 4. They are known to inhibit the growth factor, fibroblast growth factor (FGF), and may affect other growth factors as well. It is possible that Sprouty genes and the proteins they encode contribute to the patterning complex structures in vertebrates. Our laboratory studies the complex process of limb development and in particular the role that FGFs play in its patterning. The Sprouty genes are turned out in the limb at approximately the same time that FGFs are expressed. I hypothesize that Sprouty genes play a role in patterning the limb. To test this question, he has analyzed the effect of the loss of Spry4 on the development of the limb. Loss of Spry4 leads to a number of digit malformations, many of them resemble digit defects in humans. In this proposal, I will study the molecular basis for these abnormalities and determine the contribution of FGF signaling and other Sprouty genes in these digit defects. These studies will provide insights into how Spry4 affects FGF signaling and into how complex structures are normally patterned.